1. Field of the Invention
The present invention relates to a method of producing L-homophenylalanine, an angiotensin-converting enzyme (ACE) inhibitor, by reacting a L-amino acid such as L-glutamic acid with 4-phenyl-2-oxobutanoic acid in the presence of tyrosine aminotransferase.
2. Description of the Related Art
L-homophenylalanine (L-4-phenyl-2-aminobutanoic acid) is a member of a new class of oral angiotensin-converting enzyme inhibitors, which has shown a great potential as an anti-hypertension drug. Chemical or chemoenzymatical synthesises of L-homophenylalanine have been reported in various references. See Richard et al., J. Org. Chem 1998, 63: 7875; Pearson et al., J. Org. Chem., 1994, 59:2304; Richard et al., J. Chem. Soc. Perkin Trans., I, 1998, 1903; Fraser et al., Synlett, 1994, 5:379; Kijima et al., J. Chem. Tech. Biotechnol., 1994, 59:61; Ondetti et al., J. Med. Chem., 1981, 24:355; Chen et al., J. Am. Chem. Soc., 104:7294; Chen et al., Biotechnol. Lett.,1991, 13:773; Senuma et al., Apply Biochem. Biotech., 1989, 22:141.
U.S. Pat. No. 4,525,454 discloses a process for producing L-homophenylalanine by reacting 4-phenyl-2-oxobutanoic acid with L-aspartic acid in the presence of transaminase enzyme, and then decarboxylating the oxaloacetate produced therefrom. However, the process requires aspartic-glutamic transaminase as catalytic enzyme, aspartic acid as a substrate. A coupled decarboxylation reaction is also required to obtain a complete conversion.
Senuma et al., Apply Biochem. Biotech., 1989, 22:141. reported a method of converting L-2-oxo-phenylbutyric acid to L-homophenylalanine by a microbial aminotransferase. However, the report concludes that L-aspartic acid is a better substrate than L-glutamic acid because the former showed higher conversion yield than the latter. It was found that 2-oxo-4-phenylbutyric acid markedly inhibited the activity of the aminotransferase, which is not specified, and the conversion yield at more than 0.2M.